BETHESDA, Md., April 26, 2007 – In the most
comprehensive look at genetic risk factors for type 2 diabetes to
date, a U.S.-Finnish team, working in close collaboration with two
other groups, has identified at least four new genetic variants
associated with increased risk of diabetes and confirmed existence
of another six. The findings of the three groups, published
simultaneously today in the online edition of the journal Science,
boost to at least 10 the number of genetic variants confidently
associated with increased susceptibility to type 2 diabetes –
a disease that affects more than 200 million people worldwide.

“This achievement represents a major milestone in our
battle against diabetes. It will accelerate efforts to understand
the genetic risk factors for this disease, as well as explore how
these genetic factors interact with each other and with lifestyle
factors,” said National Institutes of Health (NIH) Director
Elias A. Zerhouni, M.D. “Such research is opening the door to
the era of personalized medicine. Our current one-size-fits-all
approach will soon give way to more individualized strategies based
on each person’s unique genetic make-up.”

Led by Michael Boehnke, Ph.D., of the University of
Michigan’s School of Public Health, Ann Arbor; Francis
Collins, M.D., Ph.D., of the National Human Genome Research
Institute; Richard Bergman, Ph.D., of the University of Southern
California, Los Angeles; Karen Mohlke, Ph.D. of the University of
North Carolina, Chapel Hill; and Jaakko Tuomilehto, M.D., Ph.D. of
the University of Helsinki and National Public Health Institute in
Finland; the U.S.-Finnish team received major support from the
National Institute of Diabetes and Digestive and Kidney Diseases
(NIDDK) and NHGRI’s Division
of Intramural Research, both
part of the NIH. The laboratory analysis of genetic variants
in the first stage of the study was conducted by the Center for
Inherited Disease Research, using funding from NIH and The Johns
Hopkins University in Baltimore.

The research was carried out in conjunction with the work
of two other teams: the Diabetes Genetics Initiative, which is a
collaboration of the Broad Institute of Harvard and MIT, Cambridge,
Mass.; Lund University, Malmo, Sweden; and Novartis, Basel,
Switzerland; and the Wellcome Trust Case Control Consortium/U.K.
Type 2 Diabetes Genetics Consortium. The Diabetes Genetics
Initiative was led by David Altshuler, M.D., Ph.D., Broad
Institute; Leif Groop, M.D., Ph.D., Lund University; and Thomas
Hughes, Ph.D., Novartis. The British team was led by Mark McCarthy,
M.D., FRCP, Oxford University and Andrew Hattersley, D.M., FRCP,
Peninsula Medical School, Plymouth.

“It’s been a formidable challenge to identify
the complex genetic factors involved in common diseases, such as
type 2 diabetes. Now, thanks to the tools and technologies
generated by the sequencing of the human genome and subsequent
mapping of common human genetic variations, we finally are making
significant progress,” said NHGRI Director Collins, who led
the NIH component of the Human Genome Project.

Type 2 diabetes affects nearly 21 million people in the
United States, and the incidence of the disease has skyrocketed in
the U.S. and many other developed nations over the last 30 years.
Diabetes is a major cause of heart disease and stroke, as well as
the most common cause in U.S. adults of blindness, kidney failure
and amputations not related to trauma.

NIDDK Director Griffin P. Rodgers, M.D., said, “These
genetic findings are exciting news for diabetes research. While
more work remains to be done, the newly identified genetic variants
may point us in the direction of valuable new drug targets for
the
prevention or treatment of type 2 diabetes.”

Previously known as adult onset or non-insulin dependent
diabetes (NIDDM), type 2 diabetes usually appears after age 40,
often in overweight, sedentary individuals. However, an increasing
number of younger people and even children are developing the
disease, which is characterized by the resistance of target tissues
to respond to insulin and a gradual failure of insulin-secreting
cells in the pancreas.

In addition to lifestyle factors like obesity, poor diet and
lack of exercise, doctors have long known that heredity plays a
significant role in the risk of developing type 2 diabetes. People
who have a parent or sibling with type 2 diabetes face a 3.5-times
greater risk than people without a family history of the disease.
However, researchers have only recently begun to zero in on
particular genetic variants that increase or decrease
susceptibility to the disease.

To make their discoveries, researchers used a relatively new,
comprehensive strategy known as a genome-wide association study.
“Genome-wide association studies offer a powerful way to
uncover the genetic variations that contribute to diabetes, as well
as other common conditions, such as asthma, arthritis, heart
disease, cancer and mental illnesses,” Dr. Boehnke said.
“Once susceptibility genes are identified, researchers then
can use this information to develop better approaches to detecting,
treating and preventing disease.”

To conduct a genome-wide association study, researchers use two
groups of participants: a large group of people with the disease
being studied and a large group of otherwise similar people without
the disease. Utilizing DNA purified from blood or cells,
researchers quickly survey each participant’s complete set of
DNA, or genome, for strategically selected markers of genetic
variation.

If certain genetic variations are fou
nd more frequently in
people with the disease compared to healthy people, the variations
are said to be associated with the disease. The associated genetic
variations can serve as a strong pointer to the region of the
genome where the genetic risk factor resides. However, the first
variants detected may not themselves directly influence disease
susceptibility, and the actual causative variant may lie nearby.
This means researchers often need to take additional steps, such as
sequencing every DNA base pair in that particular region of the
genome, to identify the exact genetic variant that affects disease
risk.

In the latest work, researchers began by scanning the genomes of
more than 2,300 Finnish people who took part in the Finland-United
States Investigation Of NIDDM Genetics (FUSION) and Finrisk 2002
studies. About half of the participants had type 2 diabetes and the
other half had normal blood glucose levels.

“We thank all the Finnish citizens who participated in
this study. Their generosity has created a lasting legacy that will
help to reduce the terrible toll that diabetes is taking on the
world’s health,” said Dr. Tuomilehto of the Diabetes
Unit in Finland’s National Public Health Institute.

To validate their findings, the researchers compared their
initial results with results from genome scans of 3,000 Swedish and
Finnish participants in the Diabetes Genetics Initiative and 5,000
British participants in the Wellcome Trust Case Control Consortium,
led by Peter Donnelly, D.Phil., Oxford University. After
identifying promising leads through this approach, the three
research teams jointly replicated their findings using smaller,
more focused sets of genetic markers in additional groups totaling
more than 22,000 people from Finland, Poland, Sweden, the United
Kingdom and the United States. All told, the genomes of 32,554
people were tested for the study, making it one of the largest
genome-w
ide association efforts conducted to date.

“This is a phenomenal accomplishment, in terms of both the
breadth and depth of the research. By pulling together and sharing
their data, these three groups were able to achieve far more than
any one of them could have done alone,” said Eric D. Green,
M.D., Ph.D., director of NHGRI’s Division of Intramural
Research. “This is scientific collaboration at its
best.”

Ultimately, the researchers identified four new
diabetes-associated variations, as well as confirmed previous
findings that associated six other genetic variants with increased
diabetes risk. The newly identified diabetes-associated variations
lie in or near:

·
IGF2BP2. This gene codes for a protein called insulin-like growth
factor 2 mRNA binding protein 2. Insulin-like growth factor 2 is
thought to play a role in regulating insulin action.

· CDKAL1. This
gene codes for a protein called CDK5 regulatory subunit associated
protein1-like1. The protein may affect the activity of the cyclin
dependent kinase 5 (CDK5) protein, which stimulates insulin
production and may influence other processes in the
pancreas’s insulin-producing cells, known as beta cells. In
addition, excessive activity of CDK5 in the pancreas may lead to
the degeneration of beta cells.

· CDKN2A and
CDKN2B. The proteins produced by these two genes inhibit the
activity of cyclin-dependent protein kinases, including one that
has been shown to influence the growth of beta cells in mice.
Interestingly, these genes have been heavily studied for their role
in cancer, but their contribution to diabetes comes as a complete
surprise.

· Chromosome
11. One intriguing association is located in a region of chromosome
11 not known to contain any genes. Researchers speculate that the
variant sequences may regulate the activity of genes located
elsewhere in
the genome, but more work is needed to determine the
exact relationships to pathways involved in type 2 diabetes.

The genetic variants associated with diabetes that were
confidently confirmed by the new research are: TCF7L2, SLC30A8,
HHEX, PPARG, KCNJ11 and FTO. A variant in FTO was recently
associated with increased risk of obesity. (T. Frayling et al. A
Common Variant in the FTO Gene Is Associated with Body Mass Index
and Predisposes to Childhood and Adult Obesity. Science Express,
Published online April 12, 2007) The latest study found that
variations in or near the FTO gene are also associated with greater
risk of type 2 diabetes, which is likely related to an increased
predisposition to obesity.

When the genomes of the Finnish participants were scanned for
all 10 diabetes-associated genetic variants, researchers could
identify individuals whose genetic profiles placed them at
increased risk for type 2 diabetes – including one subset of
people who faced a risk four times higher than those at the lowest
genetic risk. This “could potentially have value in a
personalized preventive medicine program,” the researchers
wrote.

However, the researchers emphasized that their predictions of
disease risk need to be interpreted with caution because the
diabetes group in their sample was “enriched” with
people who had affected siblings and because the healthy group
excluded people who had impaired glucose tolerance or impaired
fasting glucose.

NHGRI and NIDDK are two of the 27 institutes and centers at the
National Institutes of
Health, which is an agency of the Department
of Health and Human Services. The NHGRI Division of Intramural
Research develops and implements technology to understand, diagnose
and treat genomic and genetic diseases. Additional information
about NHGRI can be found at www.genome.gov . The NIDDK conducts
and supports research in diabetes and other endocrine and metabolic
diseases; digestive diseases, nutrition, and obesity; and kidney,
urologic and hematologic diseases. Additional information about
NIDDK can be found at www.niddk.nih.gov .

The National Institutes of Health -- "The Nation's Medical
Research Agency" -- includes 27 institutes and centers, and is a
component of the U.S. Department of Health and Human Services. It
is the primary federal agency for conducting and supporting basic,
clinical and translational medical research, and it investigates
the causes, treatments, and cures for both common and rare
diseases. For more, visit www.nih.gov .

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